A prospective biomarker-guided precision medicine trial of bupropion and sertraline for major depressive disorder: Sequential Multiple Assignment Randomized Trial in Depression (SMART-D)

Treatment for major depressive disorder (MDD) remains challenging as only 30% of patients respond to antidepressants in primary care. Here, we developed algorithms using predictors of response to sertraline and bupropion from a multi-site study, and tested such markers in an independent prospective clinical trial of unmedicated individuals with MDD. Leave-one-out cross-validation models achieved good performance in the training sample (AUC=0.66-0.86). In the pre-registered clinical trial, no significant differences in treatment outcomes emerged for those assigned a drug-consistent vs inconsistent with their biomarkers. However, significant differences emerged in symptom reduction trajectories for those with positive markers for both medications (response rate: 71%) or either drug (65%) compared to those with two negative markers (43%). This is the first study using biobehavioral markers to prospectively guide assignment to two widely used antidepressants. Future studies will further optimize algorithms to guide antidepressant prescription to achieve faster and stronger symptom reduction.